Aging is associated with progressive increases in cardiovascular calcification (Ngo et al., JACC Cardiovasc Imaging 2:919-927, 2009). Hemodynamically significant aortic valve stenosis affects 3% of the population over age 65 (Nkomo et al., Lancet 368:1005-1011, 2006), and patients with even moderate aortic valve stenosis (peak velocity of 3-4 m/sec) have a 5 year event-free survival of less than 40% (Amato et al., Heart 86:381-386, 2001; Rosenhek et al., Circulation 121:151-156, 2010; Briand et al., J Am Coll Cardiol 47:2229-2236, 2006; and Rosenhek et al., Eur Heart J 25:199-205, 2004). No treatments have successfully slowed progression of aortic valve calcification, and aortic valve replacement has been the only available treatment for advanced aortic valve stenosis (Bonow et al., Circulation 118:e523-661, 2008).
Progression of CAVD appears to be an active process that is fundamentally different from atherosclerosis. Re-differentiation of valvular interstitial cells to an osteoblast-like phenotype may be central to the progression of calcified lesions in stenotic valves (Miller et al., Arterioscler Thromb Vasc Biol 30:2482-2486, 2010; Miller et al., Circulation 119:2693-2701, 2009; Rajamannan et al., Circulation 107:2181-2184, 2003; and Rajamannan, Arterioscler Thromb Vasc Biol 29:162-168, 2009), and is strongly associated with increases in bone morphogenetic protein signaling (smad1/5/8 phosphorylation; Miller et al. 2010, supra; Miller et al. 2009, supra; and Yang et al., J Thorac Cardiovasc Surg 138:1008-1015, 2009), Wnt/β-catenin signaling (Shao et al., Hypertension 55:579-592, 2010; and Rajamannan et al., Circulation 112:1229-234, 2005), and transforming growth factor beta signaling (smad2/3 phosphorylation) (Xu et al., Cardiovasc Pathol 19:236-247, 2010).